The applicant's career goal is to become a physician-scientist studying translational research in age- related neurodegeneration. A comprehensive training plan with a team of mentors of diverse backgrounds will ensure the applicant's career development. The proposed studies will address the mechanism of Amyloid-beta mediated mTOR dysregulation in neurodegeneration. Alzheimer's disease (AD) is the most common cause of age-related neurodegeneration and is the sixth leading cause of death in the U.S. It is estimated that by 2050 nearly a million new cases per year will emerge, leading to a major public health crisis. The buildup of Amyloid-beta (A?) is believed to contribute to the progressive cognitive deficits in AD; however, the molecular pathways linking A? accumulation to cognitive deficits remain elusive. The goal of this proposal is to dissect the molecular pathways linking A? accumulation to cognitive deficits. Our working hypothesis is that the buildup of A? oligomers increases the activity of the mammalian target of rapamycin (mTOR) protein and exacerbates cognitive dysfunction through a ?2 adrenergic receptor (?2AR)-mediated mechanism. This hypothesis will be addressed by the following specific aims: (1) identify the molecular mechanisms underlying A?-mediated mTOR hyperactivity; and (2) determine the molecular mechanisms responsible for the ?2AR- mediated mTOR hyperactivity. We will use biochemical, pharmacological and genetic approaches to elucidate the signaling pathways linking A? to mTOR hyperactivity. These studies are innovative because they will clarify the molecular relationship between A?, ?2AR and mTOR, which has not been rigorously explored. The proposed research is significant because it will provide profound mechanistic insights into the A?-mediated mTOR dysregulation in AD pathogenesis. These findings will have an impact on the development of therapeutic approaches to modulate ?2ARs function in order to ameliorate AD pathology.